Project Summary Psoriasis is one of the most common immune-related chronic inflammatory skin disorders. Clinical observations suggest that streptococcal infection has an intimate relationship in triggering psoriasis onset and exacerbating chronic psoriasis. Humanized IL-12/IL-23 p40, IL-17A, and IL-17 receptor mAbs have shown remarkable therapeutic efficacy for the treatment of chronic plaque psoriasis, suggesting IL-23/IL-17 axis plays important roles in psoriasis pathogenesis. Our previous studies have demonstrated that dermal ?? T cells are the major IL-17 producers in the skin and are critical in psoriasis pathogenesis. Dermal ?? T cells are phenotypically and functionally unique. However, it is largely unknown how these cells are critically regulated in mice and humans, particularly in the context of microbial infection and skin microbial commensal alteration. In the proposal, we provided preliminary data suggesting that dermal ?? T cells play critical roles in skin immune surveillance and inflammation. IL-1? signaling pathway plays a crucial role in regulating dermal ?? T cell proliferation, IL-17 production, and probably trafficking in mice. Pathogen products stimulated skin cells to produce IL-1?. In addition, we showed that skin microbiota from psoriatic skin has been substantially altered compared to that in healthy control skin. Human V?9V?2 T cells were capable of secreting IL-17 and significantly decreased in the peripheral blood of psoriatic patients but increased in psoriatic skin lesions and produced large amounts of IL-17. Based on these preliminary findings, we hypothesize that dysregulated dermal ?? T cells via IL-1 signaling by pathogen infection or skin microbiota alteration play an essential role in psoriasis pathogenesis. Three Aims are proposed to address this hypothesis. Aim 1 determines the role of IL-1 signaling in psoriasis immunopathogenesis. We will test the hypothesis that IL-1 signaling regulates psoriasis immunopathogenesis through 1) directly activating dermal ?? T cells; 2) stimulating KC to secrete chemokines which chemoattract more IL-17-producing ?? T cells from periphery into dermis thus amplifying skin inflammatory cascade; 3) generating memory-like dermal ?? T cells for disease relapse. Aim 2 examines how skin commensal microorganisms regulate dermal ?? T cell homeostasis in healthy skins and dermal ?? T cell activation in skin inflammation. Aim 3 determines how human V?9 T cells are regulated by pathogen components or skin microbiota alteration for expansion and IL-17 production. Human skin/SCID mouse xenograft model will be established to determine the pathogenic roles of human V?9 T cells and microbial infection/commensal alteration in psoriasis pathogenesis. It is believed that this study will provide new insights into understanding the biology of dermal ?? T cell population and immuno-pathogenesis of psoriasis.